title: Partially-desulfated heparin improves survival in Pseudomonas pneumonia by enhancing bacterial clearance and ameliorating lung injury.
abstract: Nosocomial pneumonia (NP, or hospital-acquired pneumonia) is associated with infections originating from hospital-borne pathogens. Persistent microbial presence and acute lung injury are common features of these infections, contributing to the high mortality rates and excessive financial burden for these patients. Pseudomonas aeruginosa (PA), a gram-negative opportunistic pathogen, is one of the prominent pathogens associated with NP. PA pneumonia is characterized by excessive secretion of inflammatory cytokines, neutrophil infiltration, and subsequent lung damage. The persistent presence of PA along with overwhelming inflammatory response is suggestive of impairment in innate immunity. High mobility group box 1 (HMGB1), a recently discovered potent pro-inflammatory cytokine, plays an important role in PA lung infections by compromising innate immunity via impairing phagocyte function through toll-like receptors (TLR) TLR2 and TLR4. ODSH (2-O, 3-O-desulfated heparin), a heparin derivative with significant anti-inflammatory properties but minimal anti-coagulatory effects, has been shown to reduce neutrophilic lung injury in the absence of active microbial infections. This study examined the effects of ODSH on PA pneumonia. This study demonstrates that ODSH not only reduced PA-induced lung injury, but also significantly increased bacterial clearance. The ameliorated lung injury, together with the increased bacterial clearance, resulted in marked improvement in the survival of these animals. The resulting attenuation in lung injury and improvement in bacterial clearance were associated with decreased levels of airway HMGB1. Furthermore, binding of HMGB1 to its receptors TLR2 and TLR4 was blunted in the presence of ODSH. These data suggest that ODSH provides a potential novel approach in the adjunctive treatment of PA pneumonia.
authors.affiliation: Department of Pharmaceutical Sciences, St. John's University, College of Pharmacy and Health Sciences , Queens, NY , USA .
authors.forename: Lokesh
authors.initials: L
authors.lastname: Sharma
authors.forename: Jiao
authors.initials: J
authors.lastname: Wu
authors.forename: Vivek
authors.initials: V
authors.lastname: Patel
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Sitapara
authors.forename: Narayanam V
authors.initials: NV
authors.lastname: Rao
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Kennedy
authors.forename: Lin L
authors.initials: LL
authors.lastname: Mantell
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D058491:Bacterial Load / Q000187:drug effects; D003428:Cross Infection / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000276:immunology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D024243:HMGB1 Protein; C410523:heparin, O-desulfated; D006493:Heparin
keywords: Heparin; ODSH; Pseudomonas pneumonia; innate immunity